p53 promote oxidative stress, neuroinflammation and behavioral disorders via DDIT4-NF-κB signaling pathway

Depression is a mood disorder characterized by persistent emotional and behavioral dysregulation. Oxidative stress-induced neuronal damage is increasingly recognized as a critical risk factor contributing to the pathogenesis of depression. However, the potential molecular mechanisms and therapeutic targets underlying brain homeostasis disruption induced by neuroinflammatory responses remain unclear. The polyphenolic compound curcumin has been shown to exert neuroprotective effects and partially alleviate depression-related behavioral symptoms through its anti-oxidative properties. However, the molecular mechanisms and therapeutic targets underlying curcumin's ability to ameliorate oxidative stress-induced behavioral abnormalities in specific brain regions remain insufficiently defined. In this study, we demonstrate that chronic administration of corticosterone (CORT) induces pronounced depression- and anxiety-like behaviors in mice, accompanied by marked oxidative stress, neuroinflammation, and disrupted synaptic plasticity within the medial prefrontal cortex (mPFC). Curcumin treatment significantly ameliorated these behavioral and neuropathological abnormalities by enhancing antioxidant capacity, suppressing inflammatory cytokine production and restoring dendritic architecture. Transcriptomic profiling and network pharmacology identified the p53-DDIT4-NF-κB signaling as a key signaling hub underlying these effects. Pharmacological inhibition of p53 with pifithrin-α (PFT-α) mimicked the antidepressant-like effects of curcumin, whereas activation with NSC697923 abolished them. These findings support curcumin may serve as a promising strategy for anti-oxidative stress and anti-neuroinflammation in depression via targeting p53-DDIT4-NF-κB signaling.